Endogenous degradation enzymes such as lipases and proteolytic enzymes serve to breakdown invading organisms, antigen-antibody complexes and certain lipids and proteins that are no longer necessary or useful to the organism. In a normally functioning organism, such enzymes are produced in a limited quantity and are regulated in part through the synthesis of inhibitors.
A disturbance of the balance between enzymes and their inhibitors can lead to enzyme-mediated tissue destruction. Such destruction can occur in a variety of conditions, including inflammation, emphysema, asthma, chronic obstructive pulmonary disease (COPD), arthritis, glomerulonephritis, periodontitis, muscular dystrophy, tumor invasion and various other pathological conditions. In certain situations, e.g., severe pathological processes such as sepsis or acute leukemia, the amount of free proteolytic enzymes present increases due to the release of enzyme from secretory cells. In organisms where such aberrant conditions are present, serious damage to the organism can occur unless measures are taken to control the action of degradation enzymes.
The lungs in a human comprise 6% of the mammalian body volume and are composed of numerous small gas sacs, the alveoli. The primary purpose of the lungs is to facilitate gas interchange with the systemic circulation. The alveoli are therefore perfused by an extensive blood capillary network that brings mixed venous blood for gas exchange with fresh alveolar gas, across the pulmonary epithelial and endothelial barrier. The alveolar membrane has a total surface area of more than 100 m2 and a thickness of less than 1 μm. Diseases or conditions that cause destruction of alveolar membrane barriers can lead to fluid leakage into alveoli, resulting in loss of lung function.
For example, Acute Respiratory Distress Syndrome (ARDS) is a descriptive expression that is applied to a large number of acute, diffuse infiltrative pulmonary lesions of differing etiology that are associated with severe gas exchange disorders (in particular arterial hypoxemia). ARDS is often associated with a “leaky” capillary response. The expression “Acute Respiratory Distress Syndrome” is used because of the numerous clinical and pathological features common with Infant Respiratory Distress Syndrome (IRDS). While IRDS is associated with lung surfactant deficiency, ARDS is associated with lung surfactant malfunction. With a mortality of 50-60% (survey in Schuster Chest 1995, 107:1721-26), the prognosis of an ARDS patient is unfavorable.
To prevent or treat lung diseases, drugs may be directly delivered to the diseased tissue by bronchoalveolar lavage procedures, by liquid bolus administration through the trachea or by aerosol drug solution (e.g. by using a nebulizer) and subsequent inhalation of the aerosol droplets containing the drug. However, even where one directs the drug solution to the lungs, there are substantial uncertainties about how efficacious the drug or its administration will be. For example, the drug may be present in high concentrations in some areas while other areas receive little or no drug, the half-life of the drug in the lungs may be relatively short due to breakdown or absorption into the vascular system. There is also the problem of the effect of aerosolization on the drug. The drug may be degraded by the nebulizing action of the nebulizer or inactivated by oxidation. There is also the uncertainty concerning the ability to maintain an effective dosage for an extended period, without detrimental effect to the lungs or other organs of the host. Nor is it predictable whether a protein formulated for delivery in a dry powder form will retain its biological activity.
Pharmaceutical compositions containing some low molecular weight drugs have been delivered by pulmonary administration, most notably beta-androgenic antagonists to treat asthma Other low molecular weight non-proteinaceous compounds, including corticosteroids and cromolyn sodium, have been administered systemically via pulmonary absorption. Not all low molecular weight drugs, however, can be efficaciously administered through the lung. For example, pulmonary administration of aminoglycoside antibiotics, anti-viral drugs and anti-cancer drugs for systemic action has met with mixed success. In some cases, the drug was found to be irritating and bronchoconstrictive. Thus, even with low molecular weight substances, it is not at all predictable that the pulmonary delivery of such compounds will be an effective means of administration. See generally Peptide and Protein Drug Delivery, ed. V. Lee, Marcel Dekker, N.Y., 1990, pp. 1-11. Various factors intrinsic to the drug itself, the pharmaceutical composition, the delivery device, and particularly the lung, or a combination of these factors, can influence the success of pulmonary administration.
Hence, improvement is needed in the presently available compositions and methods for treating pulmonary conditions.